Sustained release formulations are designed to release a single dose of a pharmacologically active substance at a predetermined rate in order to maintain the effective concentration of the substance in the blood stream for a specific period of time, with minimization of the side effects caused by multiple doses.
In consideration of the therapeutic mechanism and physical and chemical properties thereof, gonadotropin-releasing hormone (GnRH) derivatives are representative of pharmacologically active substance to be designed as sustained-release formulations.
Gonadotropin-releasing hormone (GnRH) or luteinizing hormone-releasing hormone (LHRH) is a neuroendocrine peptide which is synthesized and released from neurons in the neurovascular terminal of hypothalamus. Once being released from the hypothalamus, GnRH selectively binds to specific receptors on the membrane of anterior pituitary gonadotroph cells to induce the biosynthesis and release of follicle-stimulating hormone (FSH) and leuteinizing hormone (LH). FSH and LH act to regulate the production of sex steroids from sex glands in males and females. Due to the biological functions of GnRH, its analogues may be useful for the treatment of sex hormone-dependent diseases such as prostate cancer, breast cancer, ovarian cancer, endometriosis, uterine fibroid, polycystic ovary syndrome, hypertrichosis, precocious puberty, gonadotroph pituitary adenomas, sleep apnea syndrome, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, and infertility.
Lupron® Depot is a commercially available, intramuscular or subcutaneous injection for the sustained release of the GnRH analogue leuprolide acetate, with the biodegradable PLGA [poly(lactic-co-glycolic acid)] microparticles delivering as a sustained release matrix. Generally, PLGA microparticles degrade into lactic acid and glycolic acid over a specific period of time in vivo, releasing the pharmacologically active substance loaded there within in a sustained manner (U.S. Pat. No. 5,480,656). However, not only are the fabrication processes of PLGA microparticles complicated and difficult, but also pharmacologically active substances are loaded thereinto with significantly poor efficiency. In addition, because a PLGA microparticles are difficult to filter sterilization, and melt at 40° C. or higher, the sterilization thereof cannot be achieved with general processes, but requires highly sterile conditions. An ideal sustained-release profile is obtained using two or more different PLGA microparticles which, however, further complicate the processes of fabrication and mixing (WO 2005/074896), increasing the production cost. In addition, acetic acid impurities and acidic degradation products from PLGA microparticles induce inflammation and reduce cell growth rates (K. Athanasiou, G. G. Niederauer, and C. M. Agrawal, Biomaterials, 17, 93 (1996)). For the sustained release, a suspension of 10˜100 μm PLGA microparticles in an aqueous solution is injected in a significant amount, but this gives rise to a pain or a tissue damage at the injection site.
Eligard® was introduced as a sustained-release injection formulation for a GnRH analogue (leuprolide acetate) which compensates the problems with PLGA microparticle-based sustained-release formulations. Eligard® is widely marketed as a subcutaneous injection which is prepared by dissolving PLGA [poly(DL-lactide-co-glycolide)] having a protected carboxyl terminal group and a GnRH analogue (leuprolide acetate) in N-methyl-2-pyrrolidone (NMP). Eligard® exists as a flowable composition which can be prepared by dissolving a biodegradable polymer in a polar aprotic solvent, and is designed as a subcutaneous injection with an improvement in partially drawbacks with solid PLGA microparticle formulations (U.S. Pat. No. 6,773,714). This commercial product is very poor in usability because of no supply of a complete prefilled syringes device, and exhibits low drug stability upon the mixture solution. The device provided in the product comprises two syringes which can be connected to each other, and mixing, preparing and injecting tools. A final mixture solution is not obtained until more than about 10 steps are carried out, and only 30 mins is given to an entire process from preparation to injection. In addition, the product must be stored in a refrigerator, and unless stored in a refrigerator, the final mixed solution cannot be used for more than 5 days. Moreover, no improvements are observed in the product with regard to a high initial burst, which is a drawback typical to PLGA microparticle formulations. Rather, the product exhibits higher initial burst concentration, compared to the PLGA microparticle formulation Lupron® Depot (U.S. Pat. No. 6,773,714). An initial burst concentration greatly exceeding that at which a drug can function is undesirable in both functionally and toxicologically. Particularly in consideration of the mechanism of the GnRH analogue in which the sex hormone release is temporally increased at an initial stage of administration, and then down-regulated from a certain time point, an excessive initial burst concentration must be avoided. International Patent Publication No. WO 2005/117830 describes a pre-formulation comprising at least one neutral diacyl lipid and/or at least one tocopherol, at least one phospholipid, and at least one biocompatible, oxygen containing, low viscosity organic solvent. Another alternative is described in the International Patent Publication No. WO 2006/075124 which concerns a pre-formation comprising at least one diacyl glycerol, at least one phosphatidyl choline, at least one oxygen containing organic solution, and at least one GnRH analogue. These pre-formulations allow the sustained release of a pharmacologically active substance in vivo for four weeks, and do not form lactic acid or glycolic acid degradation products from their polymer systems, thus not causing pain or inflammation. However, there is a problem with the formulations in that the use of a diacyl lipid, a component essential for the pre-formulations, as a pharmaceutical excipient is not usable and it has to be proven to be sufficiently safe, and that their obligatory organic solvent incurs a reduction in the activity of some pharmacologically active substances (H. Ljusberg-Wahre, F. S. Nielse, 298, 328-332 (2005); H. Sah, Y. Bahl, Journal of Controlled Release 106, 51-61(2005)).
Culminating in the present inventors suggested a sustained-release lipid pre-concentrate comprising a) sorbitan unsaturated fatty acid ester; b) a phospholipid; and c) a liquid crystal hardener, and a pharmaceutical composition comprising the pre-concentrate (Korean Patent Application No. 10-2012-0093677). This sustained-release lipid pre-concentrate exhibits in vivo safety and biodegradability at the same or higher levels, compared to conventional pre-concentrates and the pharmaceutical composition is found to allow for the sustained release of the pharmacologically active substance loaded therein.
Moreover, the further research of the present inventors resulted in the finding that when applied to the sustained-release lipid pre-concentrate, a GnRH analogue can be released in a sustained manner at a concentration sufficient to act as a pharmacological active substance in vivo, leading to the present invention.
A description is given of the prior arts relevant to the present invention, infra.
U.S. Pat. No. 7,731,947 describes a composition comprising: a particle formulation comprising an interferon, sucrose, methionine, and a citrate buffer, and a suspending solution comprising a solvent such as benzyl benzoate, wherein the particle formulation is dispersed in the suspending solution, elucidating the application of GnRH analogues thereto. In one Example, it is described that phosphatidylcholine is dissolved together with vitamin E (tocopherol) in an organic solvent and is used to disperse the particle formulation therein. However, this composition is different from the present invention in that the composition is used to disperse solid particles and does not allow the formation of liquid crystals.
U.S. Pat. No. 7,871,642 describes a method of preparing a dispersion for delivering a pharmacologically active substance comprising hormone formulation, dispersing a homogeneous mixture of a phospholipid, a polyoxyethylene-containing coemulsifier, triglyceride and ethanol in water, wherein the polyoxyethylene-containing surfactant is selected from among polyoxyethylene sorbitan fatty acid esters (polysorbate) and polyethoxylated vitamin E derivatives. polyoxyethylene sorbitan fatty acid esters and polyethoxylated vitamin E derivatives, derived by conjugating the hydrophilic polymer polyoxyethylene to sorbitan fatty acid ester and vitamin E, respectively, are quite different in structure from sorbitan fatty acid ester and vitamin E. They are usually used as hydrophilic surfactants utilizing the property of polyoxyethylene, which is different from the component of the present invention.
U.S. Pat. No. 5,888,533 describes a flowable composition for forming a solid biodegradable implant in situ within a body, comprising: a non-polymeric, water-insoluble, biodegradable material; and a biocompatible, organic solvent that at least partially solubilizes the non-polymeric, water-insoluble, biodegradable material and is miscible or dispersible in water or body fluids, and capable of diffusing-out or leaching from the composition into body fluid upon placement within a body, whereupon the non-polymeric material coagulates or precipitates to form the solid implant. In this composition, sterols, cholesteryl esters, fatty acids, fatty acid glycerides, sucrose fatty acid esters, sorbitan fatty acid esters, fatty alcohols, esters of fatty alcohols with fatty acids, anhydrides of fatty acids, phospholipids, lanolin, lanolin alcohols, and combinations thereof are described as the non-polymeric material, and ethanol is used as the solvent. However, differences from the present invention reside in that this composition cannot form liquid crystals and is designed to form solid implants by simple coagulation or precipitation of water-insoluble materials and that a lot of the organic solvent is necessarily used.